Summary/Abstract It is anticipated that climate change with increasing global surface temperature will be accompanied with increases in the frequency, intensity, and duration of extreme weather. Climate change and air pollution are intrinsically connected and the synergistic effects of air pollution and high temperature need to be taken into account to set up adequate public health policies and actions to face the future changes in air pollution and climate. In this study, we will test the hypothesis that diet induced obesity could enhance the interactive effects of air pollution and extreme weather. Our approach is to study the adverse cardiometabolic effects of concentrated ambient PM (CAPs, by inhalation, 6hr/d, 7d/w, for up to 6 months) with or without heat stress in mice (both male and female) on normal or high fat chow. Body core temperature as well as heart rate and heart rate variability will be monitored continuously thoughout the experiments using telemetry. Fasting blood glucose level will be measured weekly. On week 7, 15, and 23 of CAPs exposure, heat stress will be applied (6 hr/d for 7 days) to simulate a summer heat wave. In addition to continuous telemetry data, serial endpoints (24hr after the last heat stress exposure) of lung lavage, cardiac (ultrasound) and vascular function (myograph), glucose/insulin tolerance, inflammatory markers (e.g. cytokines and stress proteins) will be performed. Transcriptome analysis using RNA-seq in selected tissues (lung, heart, brain [hypothalamus], liver, spleen, fat tissues, and muscle) will also be measured. We will identify the biomarkers most closely linked to the adverse effects. After completion of these in vivo bioassays and the in silico analyses, gene function pathways that are relevant to the health effects of human exposed to air pollution and heat stress will be identified.